Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels
Por:
Sabater-Lleal, M, Huffman, JE, de Vries, PS, Marten, J, Mastrangelo, MA, Song, C, Pankratz, N, Ward-Caviness, CK, Yanek, LR, Trompet, S, Delgado, GE, Guo, X, Bartz, TM, Martinez-Perez, A, Germain, M, de Haan, HG, Ozel, AB, Polasek, O, Smith, AV, Eicher, JD, Reiner, AP, Tang, W, Davies, NM, Stott, DJ, Rotter, JI, Tofler, GH, Boerwinkle, E, de Maat, MPM, Kleber, ME, Welsh, P, Brody, JA, Chen, MH, Vaidya, D, Soria, JM, Suchon, P, van Hylckama Vlieg, A, Desch, KC, Kolcic, I, Joshi, PK, Launer, LJ, Harris, TB, Campbell, H, Rudan, I, Becker, DM, Li, JZ, Rivadeneira, F, Uitterlinden, AG, Hofman, A, Franco, OH, Cushman, M, Psaty, BM, Morange, PE, McKnight, B, Chong, MR, Fernandez-Cadenas, I, Rosand, J, Lindgren, A, Gudnason, V, Wilson, JF, Hayward, C, Ginsburg, D, Fornage, M, Rosendaal, FR, Souto, JC, Becker, LC, Jenny, NS, Marz, W, Jukema, JW, Dehghan, A, Tregouet, DA, Morrison, AC, Johnson, AD, O'Donnell, CJ, Strachan, DP, Lowenstein, CJ, Smith, NL, INVENT Consortium MEGASTROKE Cons
Publicada:
29 ene 2019
Resumen:
Background: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.
Methods: We meta-analyzed genome-wide association results from 46354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximate to 35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.
Results: We identified 13 novel genome-wide significant (P2.5x10(-8)) associations, 7 with FVIII levels (FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels (PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.
Conclusions: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
Filiaciones:
Sabater-Lleal, M:
Karolinska Univ Hosp, Karolinska Inst, Dept Med, Cardiovasc Med Unit,Ctr Mol Med, Stockholm, Sweden
IIB Sant Pau, Unit Genom Complex Dis, Barcelona, Spain
Huffman, JE:
NHLBI, Populat Sci Branch, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
de Vries, PS:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Dept Epidemiol, Human Genet & Environm Sci,Sch Publ Hlth, Houston, TX 77030 USA
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Marten, J:
Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland
Mastrangelo, MA:
Univ Rochester, Med Ctr, Aab Cardiovasc Res Inst, Rochester, NY 14627 USA
Song, C:
NHLBI, Populat Sci Branch, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Pankratz, N:
Univ Minnesota, Dept Lab Med & Pathol, Sch Med, Minneapolis, MN USA
Ward-Caviness, CK:
US EPA, Natl Hlth & Environm Effects Res Lab, Environm Publ Hlth Div, Chapel Hill, NC USA
Yanek, LR:
Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA
Trompet, S:
Leiden Univ, Dept Geriatr & Gerontol, Med Ctr, Leiden, Netherlands
Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands
Delgado, GE:
Heidelberg Univ, Med Fac Mannheim, Dept Med, Mannheim, Germany
Guo, X:
Harbor UCLA Med Ctr, Dept Pediat & Med, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA
Bartz, TM:
Univ Washington, Dept Biostat, Seattle, WA 98195 USA
Martinez-Perez, A:
IIB Sant Pau, Unit Genom Complex Dis, Barcelona, Spain
Germain, M:
Univ Paris 06, Sorbonne Univ, INSERM, UMR S 1166,Team Genom & Pathophysiol Cardiovasc, Paris, France
ICAN Inst Cardiometab & Nutr, Paris, France
de Haan, HG:
Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands
Ozel, AB:
Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
Polasek, O:
Univ Split, Fac Med, Split, Croatia
Smith, AV:
Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA
Eicher, JD:
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Reiner, AP:
Univ Washington, Dept Epidemiol, 1730 Minor Ave,Ste 1360, Seattle, WA 98101 USA
Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA
Tang, W:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Davies, NM:
Univ Bristol, Med Res Council Integrat Epidemiol Unit, Bristol, Avon, England
Univ Bristol, Bristol Med Sch, Bristol, Avon, England
Stott, DJ:
Univ Glasgow, Acad Sect Geriatr, Fac Med, Glasgow G12 8QQ, Lanark, Scotland
Rotter, JI:
Harbor UCLA Med Ctr, Dept Pediat & Med, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA
Tofler, GH:
Univ Sydney, Royal North Shore Hosp, Sydney, NSW, Australia
Boerwinkle, E:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Dept Epidemiol, Human Genet & Environm Sci,Sch Publ Hlth, Houston, TX 77030 USA
Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA
de Maat, MPM:
Erasmus MC, Dept Hematol, Rotterdam, Netherlands
Kleber, ME:
Heidelberg Univ, Med Fac Mannheim, Dept Med, Mannheim, Germany
Friedrich Schiller Univ Jena, Inst Nutr, Mannheim, Germany
Welsh, P:
Univ Glasgow, Inst Cardiovasc Med Sci, Glasgow, Lanark, Scotland
Brody, JA:
Univ Washington, Dept Med, Seattle, WA USA
Chen, MH:
NHLBI, Populat Sci Branch, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Vaidya, D:
Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA
Soria, JM:
IIB Sant Pau, Unit Genom Complex Dis, Barcelona, Spain
Suchon, P:
La Timone Hosp, Lab Haematol, Marseille, France
INSERM, UMR S 1062, Nutr Obes & Risk Thrombosis, Marseille, France
van Hylckama Vlieg, A:
Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands
Desch, KC:
Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA
Kolcic, I:
Univ Split, Fac Med, Split, Croatia
Joshi, PK:
Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland
Launer, LJ:
NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA
Harris, TB:
NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA
Campbell, H:
Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland
Rudan, I:
Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland
Becker, DM:
Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA
Li, JZ:
Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
Rivadeneira, F:
Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
Uitterlinden, AG:
Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
Hofman, A:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Harvard HT Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA
Franco, OH:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Univ Bern, Inst Social & Prevent Med, Bern, Switzerland
Cushman, M:
Univ Vermont, Larner Coll Med, Colchester, Essex, England
Psaty, BM:
Univ Washington, Dept Epidemiol, 1730 Minor Ave,Ste 1360, Seattle, WA 98101 USA
Univ Washington, Dept Med, Seattle, WA USA
Univ Washington, Dept Hlth Serv, Seattle, WA USA
Kaiser Permanente Washington, Res Inst, Seattle, WA USA
Morange, PE:
La Timone Hosp, Lab Haematol, Marseille, France
INSERM, UMR S 1062, Nutr Obes & Risk Thrombosis, Marseille, France
McKnight, B:
Univ Washington, Dept Biostat, Seattle, WA 98195 USA
Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA
Chong, MR:
McMaster Univ, Populat Hlth Res Inst, Biochem & Biomed Sci, Hamilton, ON, Canada
Fernandez-Cadenas, I:
IIB St Pau, Dept Neurol, Stroke Pharmacogen & Genet, Barcelona, Spain
Rosand, J:
Harvard Med Sch, Broad Inst, Massachusetts Gen Hosp, Boston, MA USA
Lindgren, A:
Lund Univ, Dept Clin Sci Lund, Neurol, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Neurol, Lund, Sweden
Gudnason, V:
Iceland Heart Assoc, Kopavogur, Iceland
Univ Iceland, Fac Med, Reykjavik, Iceland
Wilson, JF:
Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland
Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland
Hayward, C:
Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland
Ginsburg, D:
Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
Fornage, M:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Dept Epidemiol, Human Genet & Environm Sci,Sch Publ Hlth, Houston, TX 77030 USA
Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, Houston, TX USA
Rosendaal, FR:
Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands
Leiden Univ, Einthoven Lab Expt Vasc Med, Med Ctr, Leiden, Netherlands
Souto, JC:
Hosp Santa Creu & Sant Pau, Unit Hemostasis & Thrombosis, Barcelona, Spain
Becker, LC:
Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA
Jenny, NS:
Univ Vermont, Coll Med, Dept Pathol & Lab Med, Colchester, Essex, England
Marz, W:
Heidelberg Univ, Med Fac Mannheim, Dept Med, Mannheim, Germany
SYNLAB Acad, SYNLAB Holding Deutschland GmbH, Mannheim, Germany
Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Mannheim, Germany
Jukema, JW:
Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands
Leiden Univ, Einthoven Lab Expt Vasc Med, Med Ctr, Leiden, Netherlands
Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands
Dehghan, A:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Imperial Coll London, Dept Epidemiol & Biostat, London, England
Tregouet, DA:
Univ Paris 06, Sorbonne Univ, INSERM, UMR S 1166,Team Genom & Pathophysiol Cardiovasc, Paris, France
ICAN Inst Cardiometab & Nutr, Paris, France
Morrison, AC:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Dept Epidemiol, Human Genet & Environm Sci,Sch Publ Hlth, Houston, TX 77030 USA
Johnson, AD:
NHLBI, Populat Sci Branch, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
O'Donnell, CJ:
NHLBI, Populat Sci Branch, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston VA Healthcare Syst, Cardiol Sect Adm, W Roxbury, MA USA
Strachan, DP:
Univ London, Populat Hlth Res Inst, London, England
Lowenstein, CJ:
Univ Rochester, Med Ctr, Aab Cardiovasc Res Inst, Rochester, NY 14627 USA
Smith, NL:
Univ Washington, Dept Epidemiol, 1730 Minor Ave,Ste 1360, Seattle, WA 98101 USA
Kaiser Permanente Washington, Res Inst, Seattle, WA USA
Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs, Off Res, Seattle, WA USA
Green Published, Bronze, Green Accepted
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